US2024082340A1PendingUtilityA1

Use of riluzole prodrugs to treat alzheimer's disease

57
Assignee: BIOHAVEN THERAPEUTICS LTDPriority: Jan 18, 2021Filed: Jan 17, 2022Published: Mar 14, 2024
Est. expiryJan 18, 2041(~14.5 yrs left)· nominal 20-yr term from priority
Inventors:Vladimir CoricRobert Berman
A61K 9/4866A61P 25/28A61K 45/06A61K 38/06A61K 9/485A61K 9/4858A61P 35/00A61K 31/428
57
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Claims

Abstract

Disclosed are methods of treating a patient afflicted with Alzheimer's Disease of mild-to-moderate severity by administering to the patient a riluzole prodrug. Pharmaceutical compositions and kits including the riluzole prodrugs are also disclosed.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method of treating a patient afflicted with Alzheimer's disease of mild-to-moderate severity, comprising administering to the patient a therapeutically effective amount of a riluzole prodrug. 
     
     
         2 . The method of  claim 1 , wherein the patient is afflicted with Alzheimer's disease of mild severity. 
     
     
         3 . The method of  claim 2 , wherein the patient afflicted with Alzheimer's disease of mild severity has a Mini-Mental State Examination [MMSE] score of 20-24 at screening. 
     
     
         4 . The method of  claim 1 , wherein the patient is afflicted with Alzheimer's disease of moderate severity. 
     
     
         5 . The method of  claim 4 , wherein the patient afflicted with Alzheimer's disease of moderate severity has a Mini-Mental State Examination [MMSE] score of 14-19 at screening. 
     
     
         6 . The method of any one of  claims 1  to  5 , wherein the riluzole prodrug has the following formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein:
 R 23  is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CCH, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 OH, CH 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , CH 2 Ph, CH 2 (cyclohexyl), CH 2 (4-OH—Ph), (CH 2 ) 4  NH 2 , (CH 2 ) 3 NHC(NH 2 )NH, CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 CONH 2 , and CH 2 CH 2 CONH 2 . 
 
       
     
     
         7 . The method of any one of  claims 1  to  6 , wherein the riluzole prodrug has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of any one of  claims 1  to  7 , wherein the riluzole prodrug is administered to the patient at a dosage of from about 100 to 400 mg per day. 
     
     
         9 . The method of any one of  claims 1  to  8 , wherein the riluzole prodrug is administered to the patient at a dosage of about 110, or 140, or 150, or 210, or 280, or 350 mg per day. 
     
     
         10 . The method of any one of  claims 1  to  9 , wherein the riluzole prodrug is administered to the patient at a dosage of 280 mg, once per day. 
     
     
         11 . The method of any one of  claims 1  to  10 , wherein the riluzole prodrug is administered to the patient at a dosage of 140 mg, twice per day. 
     
     
         12 . The method of any one of  claims 1  to  11 , wherein the riluzole prodrug is administered to the patient once per day. 
     
     
         13 . The method of any one of  claims 1  to  12 , wherein the riluzole prodrug is administered to the patient twice per day. 
     
     
         14 . The method of any one of  claims 1  to  13 , wherein the riluzole prodrug is administered to the patient in the form of a capsule. 
     
     
         15 . The method of any one of  claims 1  to  14 , wherein the riluzole prodrug is administered to the patient in the form of a tablet. 
     
     
         16 . The method of any one of  claims 1  to  15 , wherein the riluzole prodrug is administered to the patient for a duration of from about 8 weeks to 48 weeks. 
     
     
         17 . The method of any one of  claims 1  to  16 , wherein the riluzole prodrug is administered to the patient for a duration of from the onset of treatment to the end of the patient's life. 
     
     
         18 . The method of any one of  claims 1 - 17 , wherein, after 48 weeks, the troriluzole treated patients (n=120) have a LS mean change from baseline of 2.3 points on the NPI score, versus 3.8 points for placebo treated (n=125) participants, [difference −1.5, 95% CI: −4.08, 1.10, p-value=0.258]. 
     
     
         19 . The method of  claim 18 , wherein the troriluzole treated patients are selected from the group consisting of only mild Alzheimer's Disease patients, only moderate Alzheimer's Disease patients, only ApoE4 positive patients, only ApoE4 negative patients, and any combination thereof. 
     
     
         20 . The method of any one of  claims 1  to  3  and  6  to  17 , wherein, after 48 weeks, the troriluzole treated participants with mild Alzheimer's Disease (n=65) may have a LS mean change from baseline of 4.2 points [95% CI: 2.7, 5.7] on the ADAS-Cog11 score, versus 4.9 points [95% CI: 3.4, 6.4] for placebo treated (n=63) participants, [difference 0.7, 95% CI: −1.4, 2.7, p-value=0.5233]. 
     
     
         21 . The method of any one of  claims 1  to  3  and  6  to  17 , wherein, after 48 weeks, the troriluzole treated participants with mild Alzheimer's Disease (n=48) may have a LS mean percent deformation change from baseline hippocampal volume of −1.1% [95% CI: −1.6, −0.6] versus −1.6% [95% CI: −2.1, −1.0] for placebo treated (n=49) participants [difference −0.5%, 95% CI: −1.2, 0.3, p-value=0.2240]. 
     
     
         22 . The method of any one of  claims 1  to  3  and  6  to  17 , wherein, after 48 weeks, the troriluzole treated participants with mild Alzheimer's Disease (n=62) may have a LS mean change from baseline of 2.1 points on the NPI score, versus 4.2 points for placebo treated (n=63) participants, [difference −2.1, 95% CI: −5.99, 1.78, p-value=0.286]. 
     
     
         23 . The method of any one of  claims 1 - 22 , wherein the treating provides an improved response in a patient. 
     
     
         24 . The method of  claim 23 , wherein the improved response is one or more of overall survival, quality of life, overall response rate, duration of response, delay of onset, or patient reported outcome. 
     
     
         25 . A method for improving a response in a patient afflicted with Alzheimer's disease of mild-to-moderate severity, comprising administering to the patient in need thereof, an effective amount of a riluzole prodrug. 
     
     
         26 . The method of  claim 25 , wherein the patient is afflicted with Alzheimer's disease of mild severity. 
     
     
         27 . The method of  claim 26 , wherein the patient afflicted with Alzheimer's disease of mild severity has a Mini-Mental State Examination [MMSE] score of 20-24 at screening. 
     
     
         28 . The method of  claim 25 , wherein the patient is afflicted with Alzheimer's disease of moderate severity. 
     
     
         29 . The method of  claim 28 , wherein the patient afflicted with Alzheimer's disease of moderate severity has a Mini-Mental State Examination [MMSE] score of 14-19 at screening. 
     
     
         30 . The method of any one of  claims 25  to  29 , wherein the riluzole prodrug has the following formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein:
 R 23  is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CCH, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 OH, CH 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , CH 2 Ph, CH 2 (cyclohexyl), CH 2 (4-OH—Ph), (CH 2 ) 4  NH 2 , (CH 2 ) 3 NHC(NH 2 )NH, CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 CONH 2 , and CH 2 CH 2 CONH 2 . 
 
       
     
     
         31 . The method of any one of  claims 25  to  30 , wherein the riluzole prodrug has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         32 . The method of any one of  claims 25  to  31 , wherein the improved response is one or more of overall survival, quality of life, overall response rate, duration of response, delay of onset, or patient reported outcome. 
     
     
         33 . A kit for treating a patient afflicted with Alzheimer's Disease of mild-to-moderate severity or improving a response in such patient, the kit comprising:
 (a) a riluzole prodrug; and   (b) instructions for administering the riluzole prodrug in the method of any one of  claims 1  to   
     
     
         33 . 
     
     
         34 . The kit of  claim 33 , wherein the patient is afflicted with Alzheimer's disease of mild severity. 
     
     
         35 . The kit of  claim 33 , wherein the patient is afflicted with Alzheimer's disease of moderate severity. 
     
     
         36 . The kit of any one of  claims 33  to  35 , wherein the riluzole prodrug has the following formula: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein:
 R 23  is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CCH, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 OH, CH 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , CH 2 Ph, CH 2 (cyclohexyl), CH 2 (4-OH—Ph), (CH 2 ) 4 NH 2 , (CH 2 ) 3  NHC(NH 2 )NH, CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 CONH 2 , and CH 2 CH 2 CONH 2 . 
 
       
     
     
         37 . The kit of any one of  claims 33  to  36 , wherein the prodrug has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         38 . A pharmaceutical composition comprising from about 40-50 weight % troriluzole, 15-20 weight % mannitol, 3-15 weight % microcrystalline cellulose, 3-15 weight % dicalcium phosphate, 5-10 weight % hydroxypropyl cellulose, 5-10 weight % crospovidone, 0.1-1 weight % colloidal silicon dioxide, and 0.1-1 weight % magnesium stearate. 
     
     
         39 . A pharmaceutical composition comprising from about 70-280 mg of troriluzole, 60-90 mg of mannitol, 30-60 mg of microcrystalline cellulose, 5-20 mg of dicalcium phosphate, 5-10 mg of hydroxypropyl cellulose, 5-20 mg of crospovidone, 0.5-5 mg of colloidal silicon dioxide, and 0.5-5 mg of magnesium stearate. 
     
     
         40 . The pharmaceutical composition of  claim 38  or  claim 39  in the form of a capsule.

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